This invention relates to certain novel compounds, their synthesis and their use for the treatment of thrombin receptor mediated diseases. More particularly, this invention relates to aminomethyl-pyrroloquinazoline compounds and pharmaceutical compositions thereof useful as thrombin receptor antagonists, methods for production thereof and methods for treating thrombin receptor mediated disorders.
Thrombin is an important serine protease in hemostasis and thrombosis. One of the key actions of thrombin is cellular modulation via receptor activation. A functional human thrombin receptor (PAR-1), cloned by Coughlin in 1991 (T.-K. Vu, Cell 1991, 64, 1057), was found to be a member of the G-protein coupled receptor (GPCR) superfamily. The receptor activation putatively occurs by N-terminal recognition and proteolytic cleavage at the Arg-41/Ser-42 peptide bond to reveal a truncated N-terminus. This new receptor sequence, which has an SFLLRN (Ser-Phe-Leu-Leu-Arg-Asn) N-terminus acting as a tethered ligand to recognize a site on the receptor, can trigger activation and signal transduction leading to platelet aggregation. Since 1991, three other protease-activated receptors with extensive homology to the thrombin receptor, xe2x80x9cPAR-2xe2x80x9d (S. Nystedt, Proc. Nat. Acad. Sci USA 1994, 91, 9208), xe2x80x9cPAR-3xe2x80x9d (H. Ishihara, Nature 1997, 386, 502), and xe2x80x9cPAR-4xe2x80x9d (W.-F. Xu, Proc. Natl. Acad. Sci USA 1998, 95, 6642), have been cloned. The thrombin PAR-1 specific antibody-induced blockade of the platelet thrombin receptor has shown efficacy against arterial thrombosis in vivo (J. J. Cook Circulation 1995, 91, 2961). Hence, antagonists of the thrombin PAR-1 are useful to block these protease-activated receptors and, as such, may be used to treat platelet mediated thrombotic disorders such as myocardial infarction, stroke, restenosis, angina, atherosclerosis and ischemic conditions.
The thrombin PAR-1 has also been identified on other cell types: endothelial, fibroblast, renal, osteosarcoma, smooth muscle, myocytes, tumor, and neuronal/glia. Thrombin activation of endothelial cells upregulates P-selectin to induce polymorphonuclear leukocyte adhesionxe2x80x94an inflammatory response of the vessel wall (Y. Sugama, J. Cell Biol. 1992,119, 935). In fibroblasts, PAR-1 activation induces proliferation and transmission of mitogenic signals (D. T. Hung, J. Cell Biol. 1992, 116, 827). Thrombin has been implicated in osteoblast proliferation through its activation of osteoblast cells (D. N. Tatakis, Biochem. Biophys. Res. Commun. 1991, 174,181). Thrombin has been implicated in the regulation and retraction of neurons (K. Jalink, J. Cell. Biol. 1992, 118, 411). Therefore, in this context, thrombin receptor antagonist compounds, particularly PAR-1 antagonists, may also be useful against inflammation, osteoporosis, cancer, neurodegenerative disorders, hypertension, heart failure, arrhythmia or glomerulonephritis.
The structure activity relationships of pyrroloquinazoline compounds as small molecule inhibitors of the intramolecular ligand of the thrombin receptor have been reported (D. A. Burnett, et al., Bioorg. Med. Chem. Lett., 1999, 2073-2077), disclosing pyrroloquinazoline compounds of the general formula: 
wherein R is selected from 4-(i-Pr)benzyl, 4-(t-Bu)benzyl, 6-(Me)naphthalen-2-ylmethyl, 4-(OEt)benzyl, 4-(Et)benzyl, 4-(SMe)benzyl, 4-(ethenyl)benzyl; NR1R2 is selected from methylamino, dimethylamino, ethylamino, ethanolamino, N-cyclopropylamino, N-methyl-N-cyclopropylamino, 1-piperidinyl, 2-1,2,3,4-tetrahydro-isoquinoline or 1-piperazinyl; and, NR3R4 is selected from amino, methylamino or dimethylamino.
U.S. Pat. No. 4,118,561 to Ledig discloses 7-(substituted) and 7,8-disubstituted pyrrolo[3,2-f]quinazoline-1,3-diamines having anti-bacterial activity of the general formula: 
wherein
(a) X is hydrogen and Y is xe2x80x94CH2R or xe2x80x94R1 wherein R is hydrogen; methyl; ethyl; n-propyl; i-propyl; n-butyl; i-butyl; n-pentyl; n-hexyl; 2-methyl-1-propenyl; cyclobutyl; cyclopentyl; cyclohexyl; 2-phenylethyl; 2-phenylvinyl; phenyl; phenyl monosubstituted in the 2-, 3-, or 4-position by chlorine, bromine, iodine, fluorine, trifluoromethyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, n-propoxy, trifluoromethoxy, cyano, methylsulfonyl, acetyl, propionyl, methylthio, ethylthio, carbethoxy, carboxyl, sodium carboxy, or potassium carboxy; phenyl monosubstituted in the 3-position by amino or nitro; phenyl disubstituted in the 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-positions by methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy, chlorine, bromine, iodine or fluorine; phenyl trisubstituted in the 2,4,6- or 3,4,5-positions by methyl, ethyl, methoxy, or ethoxy; 2,3,5,6-tetramethylphenyl; 3,4-(methylenedioxy)phenyl; 1-naphthalenyl; 2-naphthalenyl, 2-methyl-1-naphthalentyl; 1-bromo-2-naphthalentyl; 2-pyrindinyl; 3-pyrindinyl; 4-pyrindinyl; 2-quinolinyl; 8-quinolinyl; 2-thienyl; 3-thienyl; 4-thiazolyl, 3,5-dimethyl-4-isoxazolyl; tetrahydro-2-furanyl; or benzo[b]thien-3-yl; and R1 is hydrogen; phenyl monosubstituted in the 2- or 4-position by amino, nitro, cyano, acetyl, propionyl, methylsulfonyl, trifluoromethyl or carbethoxy; 2,4-dinitrophenyl; 2,4-diaminophenyl; 2-cyano-4-nitrophenyl; 2-cyano-4-aminophenyl; 3-methyl-4-nitrophenyl; 3-methyl-4-aminophenyl; 2-trifluoromethyl-4-nitrophenyl; 2-trifluoromethyl-4-aminophenyl; 2-thiazolyl; 2-pyrindinyl; 5-nitro-2-pyrindinyl; 2-pyrimidinyl; 2-pyrazinyl; 2-quinolinyl; 4-quinolinyl; 4-methyl-2-quinolinyl; 7-chloro-4-quinolinyl; 7-trifluoromethyl-4-quinolinyl; 2-methyl-4-quinolinyl; 3-methyl-2-quinoxalinyl; 2-phenyl-4-quinolinyl; or benzothiazolyl; 5-amino-2-pyrindinyl; and (b) X is methyl, phenyl, or chlorine, and Y is hydrogen, methyl, benzyl, 3-cyanobenzyl, 4-cyanobenzyl, or 2,5-dimethylbenzyl; provided that when X is phenyl, Y may only be hydrogen or methyl, and when X is chlorine, Y may only be benzyl.
The aminomethyl-pyrroloquinazoline compounds of the present invention have not been heretofore disclosed as thrombin receptor antagonists. Accordingly, it is an object of the present invention to provide aminomethyl-pyrroloquinazoline compounds useful as thrombin receptor antagonists, particularly as PAR-1 antagonists. It is another object of the invention to provide methods for producing the instant aminomethyl-pyrroloquinazoline compounds. It is a further object of the invention to provide methods for treating thrombin receptor mediated disorders, particularly PAR-1 mediated disorders including, but not limited to, inflammation, osteoporosis, hypertension, angina, atherosclerosis, thrombosis, restenosis, arrhythmia, myocardial infarction, heart failure, stroke, ischemic conditions, glomerulonephritis, cancer and neurodegenerative disorders.
The present invention is directed to structurally novel aminomethyl-pyrroloquinazoline compounds of Formula (I): 
wherein:
R1 is selected from the group consisting of aryl, heteroaryl and C3-C8 cycloalkyl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, aryl, heteroaryl, amino, amido, amidino, guanidino, hydroxy, nitro and cyano;
R2 and R3 are independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl and aryl(C1-C8)alkyl; alternatively, when independently selected from the group consisting of C1-C8 alkyl and C2-C8 alkenyl, R2 and R3 may, together with the nitrogen to which they are attached, form a saturated or partially saturated 4 to 6 membered heterocyclyl ring;
n is an integer selected from 0, 1, 2 or 3;
X is selected from the group consisting of hydrogen, xe2x80x94OR4, xe2x80x94NH2, xe2x80x94NHR4 and xe2x80x94NR4R5;
R4 and R5 are independently selected from the group consisting of C1-C8alkyl, C3-C8 cycloalkyl and aryl(C1-C8)alkyl;
Y is selected from the group consisting of halogen, xe2x80x94NH2, xe2x80x94NHR6, xe2x80x94NR6R7, xe2x80x94A1xe2x80x94NH2, xe2x80x94A1xe2x80x94NHR6, xe2x80x94A1xe2x80x94NR6R7, xe2x80x94A1xe2x80x94A2xe2x80x94NH2, xe2x80x94A1xe2x80x94A2xe2x80x94NHR6 and xe2x80x94A1xe2x80x94A2xe2x80x94NR6R7;
R6 and R7 are independently selected from the group consisting of C1-C8alkyl, C3-C8 cycloalkyl and aryl(C1-C8)alkyl; and,
A1 and A2 are independently selected from the L-amino acid residue group consisting of arginine, homoarginine, 2,4-diaminobutyric acid, lysine, ornithine, histidine, phenylalanine, homophenylalanine, naphthylalanine, cyclohexylalanine, tryptophan and tyrosine optionally substituted with one to three substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, aryl, heterocyclyl, amino, amido, amidino, guanidino, hydroxy, nitro and cyano;
and pharmaceutically acceptable salts thereof.
In an embodiment of the invention, the instant aminomethyl-pyrroloquinazoline compounds are useful thrombin receptor antagonists; in particular, useful PAR-1 antagonists.
The present invention also embodies methods for producing the instant aminomethyl-pyrroloquinazoline compounds. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Another illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Also illustrative of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier. The present invention is intended to include the use of any of the compounds described above for the preparation of a medicament for treating a thrombin or PAR-1 mediated disorder.
A further embodiment of the invention is a method for treating thrombin mediated disorders (preferably, platelet-mediated thrombotic or vaso-occlusive disorder in a subject in need thereof); in particular, a method for treating PAR-1 mediated disorders including, but not limited to, inflammation, osteoporosis, hypertension, unstable angina, atherosclerosis, arterial and/or venous thrombosis, restenosis, arrhythmia, acute myocardial infarction, heart failure, stroke, ischemic conditions, reocclusion following thrombolytic therapy and/or angioplasty, glomerulonephritis, cancer or neurodegenerative disorders.
We have discovered a structurally novel class of aminomethyl-pyrroloquinazoline compounds of Formula (I) which are unlike those known in the art in that an amino-methyl group has been positioned on the pyrrolo portion of the pyrroloquinazoline scaffold. Moreover, we have discovered that the instant aminomethyl-pyrroloquinazoline compounds are thrombin receptor antagonists; and, in particular, that the instant compounds are PAR-1 antagonists.
Embodiments of the present invention include those compounds wherein, preferably, R1 is selected from the group consisting of aryl and heteroaryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, amido, amidino, guanidino, hydroxy, nitro and cyano.
More preferably, R1 is selected from aryl optionally substituted with one to five substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, amido, amidino, guanidino, hydroxy, nitro and cyano.
Most preferably, R1 is selected from phenyl substituted with two substituents independently selected from halogen.
Embodiments of the present invention include those compounds wherein, preferably, R2 and R3 are independently selected from C1-C4 alkyl; alternatively, R2 and R3 may, together with the nitrogen to which they are attached, form a saturated 5 or 6 membered heterocyclyl ring.
More preferably, R2 and R3 are independently selected from the group consisting of methyl, ethyl and propyl; alternatively, R2 and R3 may, together with the nitrogen to which they are attached, form a saturated heterocyclyl ring selected from the group consisting of pyrrolidinyl and piperidinyl.
Most preferably, R2 and R3 are selected from methyl; alternatively, R2 and R3 may, together with the nitrogen to which they are attached, form a saturated heterocyclyl ring selected from pyrrolidinyl.
Embodiments of the present invention include those compounds wherein, preferably, n is 1.
An embodiment of the present invention includes those compounds wherein, preferably, X is selected from the group consisting of hydrogen, xe2x80x94OR4, xe2x80x94NH2, xe2x80x94NHR4 and xe2x80x94NR4R5. More preferably, X is selected from the group consisting of hydrogen, xe2x80x94OR4 and xe2x80x94NH2. Most preferably, X is selected from xe2x80x94NH2.
An embodiment of the present invention includes those compounds wherein, preferably, R4 and R5 are selected from C1-C8alkyl. More preferably, R4 is selected from the group consisting of methyl, ethyl and propyl. Most preferably, R4 is methyl.
An embodiment of the present invention includes those compounds wherein, preferably, Y is selected from the group consisting of halogen, xe2x80x94NHR6, xe2x80x94NR6R7 and xe2x80x94A1xe2x80x94A2xe2x80x94NHR6. More preferably, Y is selected from the group consisting of chlorine, xe2x80x94NHR6, xe2x80x94NR6R7 and xe2x80x94A1xe2x80x94A2xe2x80x94NHR6. Most preferably, Y is selected from the group consisting of xe2x80x94NHR6 and xe2x80x94A1xe2x80x94A2xe2x80x94NHR6.
An embodiment of the present invention includes those compounds wherein, preferably, R6 and R7 are independently selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, phenethyl and phenylpropyl. More preferably, R6 and R7 are independently selected from the group consisting of methyl, cyclopropyl and benzyl. Most preferably, R6 is selected from the group consisting of cyclopropyl and benzyl.
An embodiment of the present invention includes those compounds wherein, preferably, A1 and A2 are independently selected from the L-amino acid residue group consisting of 2,4-diaminobutyric acid and phenylalanine.
As listed in Table 1, exemplifying the invention is a compound of Formula (I) selected from:
and pharmaceutically acceptable salts thereof.
Representative Chemical Abstracts Service (CAS) Index-like names for the compounds of the present invention were derived using the ACD/LABS SOFTWARE(trademark) Index Name Pro Version 4.5 nomenclature software program provided by Advanced Chemistry Development, Inc., Toronto, Ontario, Canada.
As listed in Table 2, the invention is exemplified by a compound of Formula (Ia):
As listed in Table 3, the invention includes preferred compounds of Formula (Ia) wherein X, Y, R2 and R3 are dependently selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
The compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
The term xe2x80x9calkylxe2x80x9d refers to straight and branched-chain alkyl radical groups; similarly, alkenyl and alkynyl radicals include straight and branched chains having 2 to 8 carbon atoms or any number within this range; wherein one or two double or triple bonds are formed in the chain between adjacent members. The term xe2x80x9calkoxyxe2x80x9d refers to O-alkyl groups where alkyl is as defined supra. The term cycloalkyl refers to a cyclic alkyl ring of three to eight carbon atom members. Examples of such cyclic alkyl rings include cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term xe2x80x9cheterocyclylxe2x80x9d as used herein refers to an optionally substituted, stable, saturated or partially unsaturated 3 to 10 membered monocyclic or benzofused bicyclic ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O or S. The heterocyclyl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure and, accordingly, may be further attached to, for example, alkyl or alkoxy chains. When a hetercyclo group is further substituted, one or both rings may be optionally substituted with one to five substituents attached at any heteroatom or carbon atom which results in the creation of a stable structure.
The term aryl refers to a single aromatic ring of six carbon members or a bicyclic aromatic ring of ten carbon members. Examples of such aryl rings include phenyl and naphthyl.
The term heteroaryl refers to an aromatic monocyclic ring of five or six members or benzofused bicyclic ring system wherein at least one member is a heteroatom. Suitable heteroatoms include nitrogen, oxygen or sulfur. In the case of five-membered rings, the heteroaryl ring contains one member of nitrogen, oxygen or sulfur and, in addition, may contain up to two additional nitrogens. In the case of six-membered rings, the heteroaryl ring may contain from one to three nitrogen atoms. For the case wherein the six member ring has three nitrogens, at most two nitrogen atoms are adjacent. Examples of heteroaryl groups include, but are not limited to pyridyl, pyridazinyl, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl or quinolinyl.
The term xe2x80x9carylalkylxe2x80x9d refers to an alkyl group substituted at the terminal carbon with an aryl group (e.g., benzyl, phenethyl). The term xe2x80x9chalogenxe2x80x9d refers to a iodine, bromine, chlorine or fluorine atom.
Whenever the term xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d or either of their prefix roots appear in a name of a substituent (e.g., aryl(C1-C4)alkyl) it shall be interpreted as including those limitations given above for xe2x80x9calkylxe2x80x9d and xe2x80x9caryl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-C6) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
Under standard nomenclature rules used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. Thus, for example, a xe2x80x9cphenylC1-6alkylamidoC1-6alkylxe2x80x9d substituent refers to a group of the formula: 
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The compounds of the present invention are thrombin or PAR-1 receptor antagonists and as such are useful in treating thrombin receptor mediated disorders, particularly PAR-1 mediated disorders including, but not limited to, inflammation, osteoporosis, hypertension, unstable angina, angina, atherosclerosis, thrombosis, restenosis, reocclusion following thrombolytic therapy, reocclusion following angioplasty, arrhythmia, myocardial infarction; heart failure, stroke, ischemic conditions, vaso-occlusive disorders, glomerulonephritis, cancer and neurodegenerative disorders. These compounds are also useful as antithrombotics in conjunction with fibrinolytic therapy (e.g., t-PA or streptokinase).
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal (preferably, a mammal; most preferably, a human) who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention.
In the compounds of Formula (I), the amino acid residues comprising the A1 and A2 substituents for Y are attached to the adjacent moiety according to standard nomenclature for amino-acids (unless indicated otherwise, the amino acids bear the xe2x80x9cLxe2x80x9d absolute configuration). Accordingly, the amino-terminus (N-terminus) of the amino acid is drawn on the left and the carboxy-terminus of the amino acid is drawn on the right. In the figure below the carboxyl-terminus is drawn to the right and capped with an amine group. 
When used in the examples and throughout this application, the following amino acid abbreviations have the meanings recited hereinafter:
An example of the invention is a method of treating a thrombin receptor mediated disorder (preferably, a PAR-1 mediated disorder) selected from arterial and/or venous thrombosis, myocardial infarction, acute myocardial infarction, reocclusion following thrombolytic therapy and/or angioplasty, inflammation, unstable angina, stroke, restenosis, atherosclerosis, ischemic conditions, hypertension, heart failure, arrhythmia, glomerulonephritis, osteoporosis, cancer, neurodegenerative disorders and a variety of vaso-occlusive disorders in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. In a preferred embodiment, the therapeutically effective amount of the compound is from about 0.01 mg/kg/day to about 300 mg/kg/day.
The utility of the compounds to treat PAR-1 mediated disorders (e.g., thrombin receptor mediated disorders) can be determined according to the procedures described herein. The present invention therefore provides a method of treating PAR-1 mediated disorders in a subject in need thereof which comprises administering any of the compounds as defined herein in a quantity effective to treat PAR-1 mediated disorders. The compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
To prepare the pharmaceutical compositions of this invention, one or more compounds of Formula (I) or salt thereof as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman, et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis, et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman, et al.; published by Marcel Dekker, Inc.
In preparing a pharmaceutical composition of the present invention in liquid dosage form for oral, topical and parenteral administration, any of the usual pharmaceutical media or excipients may be employed. Thus, for liquid dosage forms, such as suspensions (i.e. colloids, emulsions and dispersions) and solutions, suitable carriers and additives include but are not limited to pharmaceutically acceptable wetting agents, dispersants, flocculation agents, thickeners, pH control agents (i.e. buffers), osmotic agents, coloring agents, flavors, fragrances, preservatives (i.e. to control microbial growth, etc.) and a liquid vehicle may be employed. Not all of the components listed above will be required for each liquid dosage form.
In solid oral preparations such as, for example, powders, granules, capsules, caplets, gelcaps, pills and tablets (each including immediate release, timed release and sustained release formulations), suitable carriers and additives include but are not limited to diluents, granulating agents, lubricants, binders, glidants, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques.
The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 300 mg (preferably, from about 0.01 mg to about 100 mg; and, more preferably, from about 0.01 mg to about 30 mg) and may be given at a dosage of from about 0.01 mg/kg/day to about 300 mg/kg/day (preferably, from about 0.01 mg/kg/day to about 100 mg/kg/day; and, more preferably, from about 0.01 mg/kg/day to about 30 mg/kg/day). Preferably, in the method for the treatment of thrombin or PAR-1 mediated disorders described in the present invention and using any of the compounds as defined herein, the dosage form will contain a pharmaceutically acceptable carrier containing between about 0.01 mg and 100 mg; and, more preferably, between about 5 mg and 50 mg of the compound; and, may be constituted into any form suitable for the mode of administration selected. The dosages, however, may be varied depending upon the requirement of the subjects, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, lozenges, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, parenteral, rectal, vaginal, inhalation or insufflation means. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
For preparing solid pharmaceutical compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents and glidants. Suitable diluents include, but are not limited to, starch (i.e. corn, wheat, or potato starch, which may be hydrolized), lactose (granulated, spray dried or anhydrous), sucrose, sucrose-based diluents (confectioner""s sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e. AVICEL(trademark) microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate and the like. Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethycellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like), water soluble or dispersible binders (i.e. alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e. TYLOSE(trademark) available from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch) and the like. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum), cross-linked polyvinylpyrrolidone and the like. Suitable lubricants and antiadherents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like. Suitable glidants include, but are not limited to, talc, cornstarch, silica (i.e. CAB-O-SIL(trademark) silica available from Cabot, SYLOID(trademark) silica available from W. R. Grace/Davison, and AEROSIL(trademark) silica available from Degussa) and the like. Sweeteners and flavorants may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drug or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.
Generally these carriers are mixed with the pharmaceutical active to form a solid preformulation composition containing a homogeneous mixture of the pharmaceutical active of the present invention, or a pharmaceutically acceptable salt thereof. Generally the preformulation will be formed by one of three common methods: (a) wet granulation, (b) dry granulation and (c)dry blending. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 mg to about 500 mg of the active ingredient of the present invention. The tablets or pills containing the novel compositions may also be formulated in multilayer tablets or pills to provide a sustained or provide dual-release products. For example, a dual release tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric materials such as shellac, cellulose acetate (i.e. cellulose acetate phthalate, cellulose acetate trimetllitate), polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylate and ethylacrylate copolymers, methacrylate and methyl methacrylate copolymers and the like. Sustained release tablets may also be made by film coating or wet granulation using slightly soluble or insoluble substances in solution (which for a wet granulation acts as the binding agents) or low melting solids a molten form (which in a wet granulation may incorporate the active ingredient). These materials include natural and synthetic polymers waxes, hydrogenated oils, fatty acids and alcohols (i.e. beeswax, carnauba wax, cetyl alcohol, cetylstearyl alcohol, and the like), esters of fatty acids metallic soaps, and other acceptable materials that can be used to granulate, coat, entrap or otherwise limit the solubility of an active ingredient to achieve a prolonged or sustained release product.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, but are not limited to aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable suspending agents for aqueous suspensions, include synthetic and natural gums such as, acacia, agar, alginate (i.e. propylene alginate, sodium alginate and the like), guar, karaya, locust bean, pectin, tragacanth, and xanthan gum, cellulosics such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, and combinations thereof, synthetic polymers such as polyvinyl pyrrolidone, carbomer (i.e. carboxypolymethylene), and polyethylene glycol; clays such as bentonite, hectorite, attapulgite or sepiolite; and other pharmaceutically acceptable suspending agents such as lecithin, gelatin or the like. Suitable surfactants include but are not limited to sodium docusate, sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer 235 and combinations thereof. Suitable deflocculating or dispersing agent include pharmaceutical grade lecithins. Suitable flocculating agent include but are not limited to simple neutral electrolytes (i.e. sodium chloride, potassium, chloride, and the like), highly charged insoluble polymers and polyelectrolyte species, water soluble divalent or trivalent ions (i.e. calcium salts, alums or sulfates, citrates and phosphates (which can be used jointly in formulations as pH buffers and flocculating agents). Suitable preservatives include but are not limited to parabens (i.e. methyl, ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethanol and the like. There are many liquid vehicles that may be used in liquid pharmaceutical dosage forms, however, the liquid vehicle that is used in a particular dosage form must be compatible with the suspending agent(s). For example, nonpolar liquid vehicles such as fatty esters and oils liquid vehicles are best used with suspending agents such as low HLB (Hydrophile-Lipophile Balance) surfactants, stearalkonium hectorite, water insoluble resins, water insoluble film forming polymers and the like. Conversely, polar liquids such as water, alcohols, polyols and glycols are best used with suspending agents such as higher HLB surfactants, clays silicates, gums, water soluble cellulosics, water soluble polymers and the like. For parenteral administration, sterile suspensions and solutions are desired. Liquid forms useful for parenteral administration include sterile solutions, emulsions and suspensions. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
Furthermore, compounds of the present invention can be administered in an intranasal dosage form via topical use of suitable intranasal vehicles or via transdermal skin patches, the composition of which are well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the administration of a therapeutic dose will, of course, be continuous rather than intermittent throughout the dosage regimen.
Compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles and the like. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines and the like.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include, but are not limited to polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, to homopolymers and copolymers (which means polymers containing two or more chemically distinguishable repeating units) of lactide (which includes lactic acid d-, l- and meso lactide), glycolide (including glycolic acid), xcex5-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylene carbonate (1,3-dioxan-2-one), alkyl derivatives of trimethylene carbonate, xcex4-valerolactone, xcex2-butyrolactone, xcex3-butyrolactone, xcex5-decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one including its dimer 1,5,8,12-tetraoxacyclotetradecane-7,14-dione), 1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels and blends thereof.
Compounds of this invention may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever treatment of thrombin mediated disorders, particularly PAR-1 mediated disorders, is required for a subject in need thereof.
The daily dose of a pharmaceutical composition of the present invention may be varied over a wide range in the subject being dosed. Preferably, the subject is a 70 kilogram (kg) adult human, having a daily dose range of from about 0.7 mg to about 21,000 mg; preferably, the range is from about 0.7 mg to about 7,000 mg per day; and, more preferably, the range is from about 0.7 mg to about 2,100 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A therapeutically effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably, the range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day; and, most preferably, from about 0.01 mg/kg to about 30 mg/kg of body weight per day. Advantageously, compounds of the present invention may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to an appropriate therapeutic level.
When used in the examples and throughout this application, the following abbreviations have the meanings recited hereinafter: